Imaging Brain Amyloid with a Bispecific Antibody

Zhang, Yun

Abstract

The dementia of Alzheimer's Disease (AD) is caused by the slow accumulation of brain amyloid. Therefore, the development of a brain scan that measures brain amyloid could identify those individuals at risk for the later development of AD. Early detection can lead to early therapy and delay the onset of symptoms. It is estimated that the delay of the onset of symptoms of AD, for just 5 years, would save $50 billion per year in U.S. health care costs. The number of people who are potential candidates for an AD diagnostic brain scan is in excess of 30 million in United States alone. The goal of this work is the development of an Alzheimer's Disease (AD) diagnostic brain scan. AD is caused by the deposition of amyloid in the brain and a diagnostic brain scan for AD could be developed if amyloid imaging agents were made transportable through the blood brain barrier (BBB). This work will prepare a genetically engineered bispecific antibody, wherein one monoclonal antibody (MAb) is a chimeric MAb to the human insulin receptor (HIR), and designated HIRMAb, and the other MAb is a single chain ScFv antibody directed at the Abeta amyloid that forms the plaque of AD, and is designated AbetaMAb. The HIRMAb will enable transport across the BBB and the AbetaMAb will bind the Abeta plaque of AD and enable imaging of the brain amyloid. The drug will contain a chelator moiety for radiolabeling with 111-indium, which will enable imaging of brain amyloid with single photon emission computed tomography, which is widely available in most hospitals and imaging centers. In phase I, the fusion gene will be engineered, cell lines will be transfected, and the bi-functionality of the fusion protein will be demonstrated, as it will be shown that the fusion protein both binds the BBB receptor and binds the AD amyloid. This work will enable the preparation of an IND to the FDA for testing of this novel in vivo brain scan that will be the first diagnostic test specific for AD. The AD brain scan may allow for early detection of those individuals at risk for later development of brain amyloid and AD, and permit early drug therapy.